Plasma HDL cholesterol and apoA-I are inversely correlated with the development of premature cardiovascular disease (CVD). Current screening programs testing HDL levels will identify individuals with low HDL that require evaluation for increased CVD risk. Not all individuals with low HDL are at increased CVD risk. Genetic diseases characterized by low levels of HDL not associated with markedly increased CVD risk include LCAT deficiency, Fish Eye Disease, and Tangier disease. Recently we identified kindreds with familial hypoalphalipoproteinemia (F Hypoalpha) with HDL from 7 to 15 mg/dl and no premature CVD. We have performed radiolabeled LpA-I, and LpA-I:A-II kinetic studies in patients with LCAT deficiency, and familial hypoalphalipoproteinemia without heart disease. LpA-I and LpA-I:A-II, the two major lipoprotein particles in HDL, differ in their protection against CVD. Several lines of evidence indicate that LpA-I not LpA-I:A-II is the major antiatherogenic lipoprotein particle in HDL. In kinetic studies of LCAT deficient patients the catabolism of apoA-I on LpA-I:A-II is significantly faster that of apoA-I on LpA-I resulting in a selective proportional decrease in the plasma levels of LpA-I:A-II. Thus there is a relatively sparing effect on the reduction of plasma LpA-I levels. This may be one of the potential mechanisms for the reason that patients with LCAT deficiency with low HDL are not at increased risk for premature cardiovascular disease. Kinetic studies in five F Hypoalpha probands without CVD revealed that both LpA-I and LpA-I:A-II are rapidly catabolized leading to low HDL levels. Catabolism of LpA-I:A-II is slightly faster than LpA-I leading to a normal or increased ratio of plasma LpA-I/LpA-I:A-II. The combined results from these studies have clearly shown that hypoalphalipoproteinemia is heterogeneous and that not all patients with low HDL have an increased risk of premature CVD. Metabolic studies have shown that the metabolism of LpA-I and LpA-I:A-II are effected independently LCAT deficiency and F Hypoalpha patients. These data will provide new approaches to the identification of which individuals with low HDL are at increased risk of premature CVD.